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Pathology Department, Washington Hospital Center, Washington, D.C. 20010-2975
Address all correspondence and requests for reprints to: Yolanda C. Oertel, M.D., Pathology Department (C-1219), Washington Hospital Center, 110 Irving Street NW, Washington, D.C. 20010-2975. E-mail: . yolanda.c.oertel{at}medstar.net
Abstract
Fine-needle aspiration has become the diagnostic tool of choice in the initial evaluation of thyroid nodules. As a cytopathologist who has been performing fine-needle aspirations for over 25 yr at a university hospital and for the last 3 yr at the largest not-for-profit hospital in the Washington, D.C. area, I have seen increasing demand for this service. However, there is also discontent with the cytopathology reports issued by numerous laboratories. Pathologists have to standardize and simplify their reports so that they will be more meaningful to the referring physician. Endocrinologists should communicate their needs to the pathologists and insist on clear, succinct, and prompt diagnoses.
ALL DECISIONS REGARDING therapy and prognosis of patients are based on diagnosis. Endocrinologists are using fine-needle aspirations (FNAs) of the thyroid more often to evaluate thyroid nodules and to decide on the subsequent management of their patients. There are three principal problems that are encountered frequently: 1) whether the specimen is adequate; 2) whether it is representative of the lesion; and 3) whether the cytopathology report is understandable.
Is the aspirated material adequate or satisfactory for cytologic diagnosis?
The material should be sufficient in amount and of good technical quality to allow a cytologic interpretation. Pathologists are still struggling to reach an accord on what constitutes an adequate sample, both in terms of the amount of material and the quality of the smears. Although this is beyond the scope of the present paper, I believe a statement about the quality of the aspirate is a necessary part of the cytopathology report.
This topic has been addressed in the pages of this journal (1, 2). Hamburger stated that "at least six clusters of benign cells on each of at least two slides prepared from separate aspirates" are needed. I do not believe that a cell count is enough for determining the adequacy of the specimen. The pathologist should know how to count, but it is more important that the pathologist knows what counts. Let me reiterate: if the pathologist needs to count the number of cells present in the smears, then I believe the specimen is unsatisfactory. There should be so many cells to examine that counting them would be a waste of time. There are very few exceptions that confirm this rule. For example: Several aspirations are performed from an enlarged and firm thyroid gland by an experienced aspirator applying proper suction. The smears show many fragments of fibrocollagenous tissue, some lymphoid cells, and a few sheets of small follicular cells. This is an adequate sample of the fibrotic phase of Hashimoto’s thyroiditis. The cytopathology report should be followed by a comment regarding the scant cellularity, such as: "Cytopathology Diagnosis: Scant benign aspirates most consistent with Hashimoto’s thyroiditis with extensive fibrosis. See comment (Comment: Six aspirates were performed with 22-, 23-, and 25-gauge needles and maximum suction. Cellular material is scant because of the extensive fibrosis.)."
Is the aspirated material representative of the lesion?
This is more easily determined if the pathologist interpreting the smear is also the one aspirating the patient. Otherwise, the aspirator must provide the pathologist detailed information regarding the size and characteristics of the lesion in question, relevant clinical data, and a differential clinical diagnosis.
An aspirate may be adequate for cytologic interpretation, but it may not be representative of the lesion in question. Hence, the cytologic diagnosis will be incorrect. For example, if aspirates from a small firm nodule reveal only benign follicular cells and thin colloid, one has to be suspicious that the needle was not placed in the lesion. Those cells and the thin colloid do not explain the firmness of the lesion. Additional aspirates have to be performed to rule out a papillary carcinoma.
As another example, two submitted smears may contain some sheets of follicular cells, colloid, cholesterol crystals, and some macrophages. If the nodule was soft and 1 cm in diameter or less, the two smears may be representative and suggest a cystic lesion. If the mass is 3 cm in diameter, however, this is not an adequate sample.
Advocates of ultrasound-guided FNA indicate that this imaging technique helps assure that the aspirate is representative of the lesion in question. I believe that this modality should be reserved for nonpalpable lesions. It has been my experience (at two separate institutions, and also diagnosing material submitted from a free-standing radiology center) that the specimens are extremely variable. The samples are operator-dependent. The rate of unsatisfactory specimens is usually high. I see many patients for a repeat FNA after they have had the procedure done under ultrasound guidance. They complain about how painful it was, how long it took, and the subsequent hematoma. Recently, I had a patient who underwent ultrasound-guided FNAs on two separate occasions; both failed to obtain diagnostic material. She consulted one of our endocrinologists for a second opinion. She had been told not to worry about her thyroid lesion, and that because no cells had been obtained, it had to be benign. I accepted this patient as a walk-in and diagnosed her with papillary carcinoma (within the hour). This was confirmed on thyroidectomy.
There are many other issues related to FNA and ultrasound of the thyroid that I believe deserve a more thorough discussion in a combined forum (radiologists, pathologists, surgeons, and endocrinologists).
Is the cytologic diagnosis stated clearly?
Cytopathology reports vary from one institution to another and even within the same institution (according to the pathologist or cytopathologist who makes the diagnosis). Because of restrictions imposed by managed care, FNA samples often are sent to distant laboratories. Hence, the endocrinologist cannot drop by the pathologist’s office and ask about the meaning of the report. I have heard complaints from my colleagues about nebulous reports, and I have been shown reports that they want me to decipher for them.
For example: a report reads as follows, "Cytologic Diagnosis: No malignant cells seen. The smears contain only blood and macrophages. No follicular cells are present." The cytologic diagnosis in this instance should read, "Unsatisfactory specimen for cytologic diagnosis." Hence, the pathologist has not expressed clearly that the aspirate has not provided any useful information.
A cytologic diagnosis should be straightforward. When this is not possible, the pathologist must add a comment indicating why a definitive diagnosis cannot be reached.
For example: "Cytologic Diagnosis: Follicular lesion, favor hyperplasia. A follicular neoplasm cannot be ruled out." This diagnosis requires the addition of a comment or an additional explanation.
If an entity is diagnosed or classified in an idiosyncratic manner, this will limit the usefulness of the pathology report and impair our understanding of the disease. As long as this subject remains neglected, endocrinologists will feel frustrated by obscure reports on fine-needle aspirates of the thyroid gland. Standardized terminology is the foundation for effective communication. We are aware that this is not a simple task. Efforts have been made to accomplish this goal (3, 4), but the problem persists. The broad spectrum of follicular lesions of the thyroid has made this particularly difficult. For example, one pathologist’s adenomatoid nodule (generally considered a nonneoplastic entity) may be diagnosed by a different pathologist (who does not apply the strict criteria) as an adenoma (usually considered a true neoplasm).
Management of the patient depends, to a large extent, on an accurate diagnosis interpreted correctly. The diagnosis may be stated correctly, but it may not be interpreted correctly (sometimes with untoward consequences). The pathologist believes that the clinicians will understand the report or will interpret the report appropriately. Recently, we have become more aware that this might not be true (5, 6).
Common cytologic diagnoses (7)
Adenomatoid nodule with abundant colloid (colloid-rich adenomatoid nodule, colloid nodule, hypocellular adenomatoid nodule).
This is the most common of the nodules. If the pathologist has performed the aspirations, and the nodules are multiple and/or bilateral, the report will read, "Adenomatoid nodules most consistent with multinodular goiter." If the pathologist is interpreting submitted smears and does not know whether it is a single nodule or multiple nodules (and therefore, has not palpated the gland), the report will read, "Adenomatoid nodule(s) with abundant colloid."
Cellular adenomatoid nodule (adenomatoid nodule with hypercellularity, hyperplastic nodule, parenchymatous nodule, cell-rich nodule) (8).
The smears are very cellular. The follicular cells are usually slightly enlarged and arranged in sheets, clusters, some rosettes, and tubules. The colloid is scant. These lesions should be followed closely to avoid a false negative diagnosis. If the patient has not received suppressive therapy, such therapy might be considered and then the FNA repeated in 6–8 months (I believe that we should be more selective in choosing which patients might benefit from suppression, based on FNA findings, rather than using it indiscriminately. Do not expect colloid-rich nodules to respond; instead, try suppressing the cellular lesions. I have suggested frequently that a systematic study be performed in which only patients diagnosed with cellular adenomatoid nodules be given suppressive therapy. This has fallen on deaf ears).
Cellular adenomatoid nodule vs. follicular neoplasm (8).
The smears are very cellular, and the follicular cells are enlarged and arranged predominantly in rosettes and tubules. Colloid is scant. Many tissue fragments usually are present. Microfollicles, with or without inspissated colloid, sometimes are seen. We believe that these patients should either undergo a suppressive trial with repeat FNA in 6–8 months or else have surgical excision.
Follicular neoplasm (excluding oxyphilic cell type).
The smears contain microfollicles with inspissated colloid in their lumens. The background is hemorrhagic and usually devoid of colloid. Because the distinction between follicular adenoma and follicular carcinoma rests on the identification of capsular and/or vascular invasion, we make no attempt to distinguish between them cytologically. These patients should undergo surgery.
Follicular neoplasm of oxyphilic cell type (Hürthle cell type).
The smears contain a monotonous population of cells with abundant oxyphilic cytoplasm and nuclei with conspicuous nucleoli. Binucleated cells are common. A Hürthle cell adenoma cannot be distinguished from a Hürthle cell carcinoma on FNA smears, so these patients should have surgery.
Hashimoto’s thyroiditis.
Other synonyms include focal chronic lymphocytic thyroiditis, autoimmune thyroiditis. Cytologically, there is an overlap with Graves’ disease. The patient may present with a single nodule (mimicking a neoplasm) and may lack antibodies to thyroid peroxidase and Tg.
Hashimoto’s is the leading source of false positive diagnoses. The increased number of follicular cells, the numerous Hürthle cells, and the presence of atypical lymphoid cells may lead to an equivocal diagnosis of papillary carcinoma, follicular neoplasm of Hürthle cell type, or malignant lymphoma.
Medullary carcinoma.
Although rare, medullary carcinoma can be diagnosed with relative ease on FNA smears. It is important to make this specific diagnosis and to rule out the presence of a pheochromocytoma before thyroidectomy. There is an overlap in the cytologic features of Hürthle cell neoplasm and medullary carcinoma. Cytoplasmic eosinophilia and binucleation are common in both entities. When there is uncertainty, a serum calcitonin should be determined. In our experience, immunocytochemical stains for calcitonin are not very reliable on smears. Results are more consistent and reliable if paraffin sections from cellblocks are used for this purpose. I prefer to request a serum calcitonin assay, because it is faster and cheaper for confirmation of my diagnosis.
Papillary carcinoma, the most frequent thyroidal carcinoma.
Some histologic subtypes can be diagnosed on aspirates also. Most smears are markedly cellular and contain enlarged cells with dense cytoplasm and well-demarcated cellular borders. Intranuclear cytoplasmic pseudoinclusions, psammoma bodies, multinucleated histiocytes, and nuclear grooves (in Papanicolaou stained material) are common findings in the classic papillary carcinomas but are less frequent in the follicular variant (9). Most institutions report a very high accuracy of this diagnosis.
Undifferentiated or anaplastic carcinoma, a highly malignant tumor, especially affecting elderly women.
If only a few aspirates are performed (limited sampling), FNA may be a source of false negative diagnosis because of necrosis, hemorrhage, or extensive fibrosis. Smears often contain markedly atypical epithelial cells (mono- or multinucleated), some bizarre nuclei, spindled cells, and osteoclast-like multinucleated cells.
In summary, there are two issues that I believe are relevant: 1) Does the endocrinologist understand what the pathologist means? The purpose of this paper is to help answer this question. 2) Does the pathologist know what the endocrinologist needs or expects from a report? I will need your help with this second issue. You, the reader, will have to tell me what you need, either by letter or e-mail.
Pathologists should strive for improving communication with the referring endocrinologists by providing prompt, clear, and succinct diagnoses. Endocrinologists should express their needs to the pathologists so these can be met. Remember that FNA is another diagnostic tool in your armamentarium, but it is no substitute for clinical judgment. "Diagnosis by aspiration is as reliable as the combined intelligence of the clinician and pathologist makes it" (10).
Acknowledgments
I am grateful to Kenneth Burman, M.D., Director, Section of Endocrinology, Washington Hospital Center, for having encouraged me to write this article; and to my husband, James E. Oertel, M.D., for editorial assistance.
Footnotes
Y.C.O. is Senior Staff Pathologist and Director, Fine Needle Aspiration Service, Washington Hospital Center, Washington, D.C.; Professor Emerita of Pathology, The George Washington University School of Medicine and Health Sciences, Washington, D.C.; and Adjunct Professor of Pathology and Laboratory Medicine, School of Medicine, MCP Hahnemann University, Philadelphia, Pennsylvania.
Abbreviation: FNA, Fine-needle aspiration.
Received October 22, 2001.
Accepted January 10, 2002.
References
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  K. Krohn, D. Fuhrer, Y. Bayer, M. Eszlinger, V. Brauer, S. Neumann, and R. Paschke Molecular Pathogenesis of Euthyroid and Toxic Multinodular Goiter Endocr. Rev., June 1, 2005; 26(4): 504 - 524. [Abstract] [Full Text] [PDF]
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 D Fuhrer, M Eszlinger, S Karger, K Krause, C Engelhardt, D Hasenclever, H Dralle, and R Paschke Evaluation of insulin-like growth factor II, cyclooxygenase-2, ets-1 and thyroid-specific thyroglobulin mRNA expression in benign and malignant thyroid tumours Eur. J. Endocrinol., May 1, 2005; 152(5): 785 - 790. [Abstract] [Full Text] [PDF]
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